Pujol, Pascal

LBA504 Background: Limited efficacy and serious toxicities have limited uptake of tamoxifen or raloxifene as preventatives of breast cancer. Aromatase inhibitors (AIs) prevent contralateral breast cancers more than tamoxifen in adjuvant trials and have fewer serious side effects. This is the first report of an AI used in primary prevention. Methods: NCIC CTG MAP.3 is a randomized trial designed to detect a 65% reduction in annual incidence of invasive breast cancer (IBC) on exemestane (E) versus placebo (P). Eligible postmenopausal women had ≥ one of the following risk factors: Gail score >1.66%, prior ADH, ALH, LCIS or DCIS with mastectomy, age over 60. Health-related and menopause-specific quality of life (QOL) were assessed by SF-36 and MENQOL questionnaires. Results: From 2004-2010, 4,560 women were randomized: age 62.5 yrs (37-90); Gail Score 2.3 % (0.6-21); BMI 28.0 kg/m2 (15.9-65.4). Risk factors included: age >60 yrs (49%); Gail score >1.66 (40%); and prior ADH, ALH, LCIS or DCIS with mastectomy (11%). At median follow-up of 35 months there were 11 IBCs on E and 32 on P (annual incidence 0.19% vs 0.55%; HR= 0.35, 95% CI 0.18-0.70, p = 0.002); ductal (10E/27P), lobular (1E/5P). Most tumors were ER positive (7E/27P); Her2/neu negative (10E/26P); TNM stage T1 (8E/28P), N0 (7E/22P), M0 (11E/30P). E was superior in all subgroups: by Gail score, age, BMI, prior LCIS and DCIS. The annual incidence rate of IBC or DCIS was 0.35% E and 0.77% P (HR=0.47;95% CI 0.27-0.79; p = 0.004) based on 64 IBCs or DCISs (20E/44P). Clinical bone fractures, osteoporosis, hypercholesterolemia or cardiovascular events were equal in both arms. No clinically meaningful differences in QOL were detected. Conclusions: Exemestane significantly reduced invasive and pre-invasive breast cancers in postmenopausal women at increased risk for breast cancer with no serious toxicities. Exemestane should be considered a new option for primary prevention of breast cancer. Supported by the Canadian Cancer Society; Pfizer Inc. PEG supported in part by Avon Foundation.

Abstract Background:BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. Cancer Epidemiol Biomarkers Prev; 24(1); 308–16. ©2014 AACR.

Abstract Background: Exemestane, a steroidal aromatase inhibitor, reduced the incidence of invasive breast cancers by 65% among 4560 post-menopausal randomized to exemestane or placebo for 5 years on MAP.3. Differences in quality of life (QOL) were judged to be minimal, but only summary information was reported. Purpose: To provide more detailed information about effects of exemestane on menopause-specific and health-related qualities of life. Method: Participation in quality of life assessment was an eligibility criterion. Menopause-specific and health-related qualities of life were assessed using the MENQOL (4 scales; physical, vasomotor, psychosocial, sexual) and SF-36 (8 scales; physical health, role function — physical, bodily pain, general health, vitality, social function, role function — emotional, mental health, and 2 summary scales) instruments, respectively at baseline, 6 months and then yearly after randomization. Compliance with QOL questionnaire completion at each follow-up visit ranged from 93–98%, and did not differ by group. Change scores for each MENQOL and SF-36 scale, calculated for each assessment time relative to baseline, were compared using the Wilcoxon Rank-Sum test. Summary scores were used to summarize the QOL scores observed at each time point for each SF-36 dimension and overall mental (MCS) and physical component summaries (PCS) and MENQOL domains. Clinically important worsening of MENQOL change scores was defined as an increase of ≥0.5/8 points. SF-36 change scores were considered worsened if scores decreased by ≥ 5 points from baseline. Results: Both groups were balanced on scores for MENQOL and SF-36 at baseline. Median follow-up was 35 months and the proportion of women who stopped study medication early for toxicity reasons was 15% in the exemestane arm and 11% in the placebo arm. There was a statistically significant difference in change scores for vasomotor symptoms among women on exemestane during the first 4 years (p-values <0.01), compared to placebo. However, no between-group differences in vasomotor change met the criterion for clinical importance. Women on exemestane had statistically poorer sexual functioning (mean change = −0.02, SD=1.37) compared to placebo (mean change = −0.12, SD=1.32) during the first 6 months on study (p-value = 0.03) but the differences were not statistically significant thereafter or clinically important at any time. Among the 8 SF-36 scales, only bodily pain was statistically different between exemestane and placebo for the first 24 months on study medication (p-value <0.01), but no between-group difference in change scores exceeded 5 points. Overall SF-36 PCS and MCS assessing changes in overall physical and mental health-related QOL did not differ significantly by group at any assessment. Conclusion: Our assessment that early differences in vasomotor symptoms and pain were probably not clinically important is supported by the observation of no between-group differences when overall physical and mental health-related QOL changes were compared. Exemestane does not appear to have a major negative impact on the quality of life among these women. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S6-1.

Abstract Background: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Methods: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. Results: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07–1.27; P = 7.42 × 10−4] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73–0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94–1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05–1.29; P = 3.8 × 10−4) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10–1.52; P = 1.8 × 10−3). Conclusions: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. Impact: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(4); 645–57. ©2012 AACR.